Process for preparing enantiomerically pure imidazo[4,5,1-JK][1,4]-benzodiazepin-2(1H)-thiones

ABSTRACT

Process for preparing enantiomerically pure imidazo[4,5,1-jk][1,4]benzodiazepin-2(1H)-thiones of formula ##STR1## starting from 2,6-dihalo-3-nitrobenzyl derivatives (II) and suitably N-protected 1,2-diaminopropanes (III) ##STR2## Novel enantiomerically pure intermediates of formula (III) and (IV) prepared in the course of the present process.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is based upon PCT application No. PCT/EP 92/02171,filed Sep. 18, 1992, which claims priority from EPO application Ser. No.91.202.474.2, filed Sep. 24, 1991.

BACKGROUND OF THE INVENTION

In EP-A-0,348,522; Nature 1990, 343, 470; J. Med. Chem. 1991, 34, 746;and The Lancet 1991, 338, 140 there are described4,5,6,7-tetrahydroimidazo[4,5,1-jk]-[1,4]benzodiazepin-2(1H)-thiones(TIBO) derivatives with potent activity against human immunodeficiencyvirus 1 (HIV-1) in vitro and showing encouraging results in vivo. Asignificant limitation to further assessment and eventual large-scaleproduction of these novel drugs has hitherto been their long, difficultand insufficient synthesis. The fundamental problem in all approaches tothe title compounds reported up till now relates to the use of benzoicacid derivatives and/or amino acid derivatives as starting materials.All said approaches necessarily involve one or two amide-to-aminereduction steps with violently reacting reagents such as lithiumaluminum hydride or borane derivatives. Whereas such approaches may besuitable in the laboratory, (e.g.J. Org. Chem. 1991, 56, 4600), they arehardly amenable to large-scale production. In case enantiomeric aminoacid derivatives are used as starting materials, the problems arefurther compounded by the possibility of racemisation at the chiralcarbon atom.

The present invention is concerned with an improved process forpreparing particular TIBO derivatives that avoids all problematicamide-to-amine reductions and rules out any possibility of racemisationat the chiral carbon atom. The process according to the presentinvention also represents a short and efficient industrial approach toparticular TIBO compounds reported hitherto.

DESCRIPTION OF THE INVENTION

The present invention is concerned with a process of preparingenantiomerically pure 8-halo-4,5,6,7-tetrahydro-5-methylimidazo[4,5,1-jk]-[1,4]benzodiazepin-2(1H)-thione derivatives having the formula##STR3## and the pharmaceutically acceptable acid addition salt formsthereof, wherein

R represents halo; and

L represents C₃₋₇ alkenyl.

Said process is especially interesting for the preparation of(S)-8-halo-4,5,6,7-tetrahydro-5-methylimidazo[4,5,1-jk][1,4]benzodiazepin-2(1H)-thionederivatives having the formula ##STR4## and the pharmaceuticallyacceptable acid addition salt forms thereof, wherein

R in particular represents chloro or bromo; and

L in particular represents 3-methyl-2-butenyl or 3-ethyl-2-pentenyl.

The process according to the present invention is exceedinglyinteresting for the preparation of(S)-8-chloro-4,5,6,7-tetrahydro-5-methyl-6-(3-methyl-2-butenyl)-imidazo[4,5,1-jk][1,4]benzodiazepine-2(1H)-thionehaving the formula ##STR5## In the foregoing definitions and hereinafterthe term `enantiomerically pure` concerns compounds having anenantiomeric excess of at least 94% (i.e. minimum 97% of one enantiomerand maximum 3% of the other enantiomer) up to an enantiomeric excess of100% (i.e. 100% of one enantiomer and none of the other), in particularcompounds having an enantiomeric excess of 96% up to 100%, more inparticular having an enantiomeric excess of 98% up to 100%; the term`halo` defines fluoro, chloro, bromo, iodo, in particular chloro orbromo and especially chloro; the term `C₃₋₇ alkenyl` defines straightand branched hydrocarbon radicals containing one double bond and havingfrom 3 to 7 carbon atoms such as, for example, 2-propenyl, 2-butenyl,3-butenyl, 2-methyl-2-propenyl, 3-methyl-2-butenyl, 3-ethyl-2-pentenyland the like, in particular 3-methyl-2-butenyl and 3-ethyl-2-pentenyl.The compounds of formula (I) have basic properties and, consequently,they may be convened to their therapeutically active non-toxic acidaddition salt forms by treatment with appropriate acids, such as, forexample, inorganic acids, e.g. hydrochloric, hydrobromic and the likeacids, sulfuric acid, nitric acid, phosphoric acid and the like; ororganic acids, such as, for example, acetic, propanoic, hydroxyacetic,2-hydroxy-propanoic, 2-oxopropanoic, ethanedioic, propanedioic,butanedioic, (Z)-2-butenedioic, (E)-2-butenedioic, 2-hydroxybutanedioic,2,3-dihydroxybutanedioic, 2-hydroxy-1,2,3-propanetricarboxylic,methanesulfonic, ethanesulfonic, benzenesulfonic,4-methylbenzenesulfonic, cyclohexanesulfamic, 2-hydroxybenzoic,4-amino-2-hydroxy-benzoic and the like acids. Conversely the salt formcan be converted by treatment with alkali into the free base form. Theterm pharmaceutically acceptable acid addition salts also comprises thesolvates which the compounds of formula (I) may form. Examples of suchsolvates are e.g. the hydrates, alcoholates and the like.

In particular, the present invention concerns a process of preparing thecompounds of formula (I) as defined hereinabove, characterized by

(o) selectively protecting enantiomerically pure 1,2-diaminopropane byreaction with a protecting agent of formula P--W, wherein P represents aprotective group such as, for example, a sulfonyl group, e.g.methanesulfonyl, trifluoromethanesulfonyl, benzenesulfonyl, 2- or4-nitrobenzenesulfonyl, 4-methylbenzenesulfonyl,2,6-dimethylbenzenesulfonyl and the like, or an acyl group, e.g. formyl,methylcarbonyl, tert. butylcarbonyl and the like, and W represents areactive leaving group such as, for example, halo, e.g. chloro, bromo oriodo, or a sulfonyloxy group, e.g. methanesulfonyloxy,trifluoromethanesulfonyloxy, benzenesulfonyloxy,4-methylbenzenesulfonyloxy, 2-naphthalenesulfonyloxy and the likeleaving groups, optionally in a reaction-inert solvent, to yield anintermediate of formula (III), ##STR6## (i) reacting a2,6-dihalo-3-nitrobenzyl derivative of formula (II) wherein R representshalo as defined hereinbefore and W represents a reactive leaving groupsuch as, for example, halo, e.g. chloro, bromo or iodo, or a sulfonyloxygroup, e.g. methanesulfonyloxy, trifluoromethanesulfonyloxy,benzenesulfonyloxy, 4-methylbenzenesulfonyloxy, 2-naphthalenesulfonyloxyand the like leaving groups, with an enantiomerically pure N¹ -protected1,2-diaminopropane derivative of formula (III) in a reaction inertsolvent, such as, for example, a halogenated hydrocarbon, e.g.dichloromethane, trichloromethane, an ether, e.g. tetrahydrofuran,1,4-dioxane, an alcohol, e.g. propanol, 1-butanol, 4-methyl-2-pentanol,a dipolar aprotic solvent, e.g. N,N-dimethylformamide,N,N-dimethylacetamide, dimethyl sulfoxide, and the like, or a mixture ofsuch solvents in the presence of a base such as, for example, an alkalimetal carbonate or hydrogen carbonate, e.g. sodium carbonate or sodiumhydrogen carbonate, or an organic base such as, for example,N,N-diethylethanamine, N-(1-methylethyl)-2-propanamine and the like,##STR7## (ii) deprotecting the thus obtained intermediate of formula(IV) in an acidic medium such as, for example, hydrobromic acid orpreferably, concentrated sulfuric acid, by hydrolysis, thus yielding anintermediate of formula (V), which optionally may be isolated as an acidaddition salt, ##STR8## (iii) cyclizing the amine of formula (V) or anacid addition salt form thereof to a benzodiazepine of formula (VI) bytreatment with a base such as, for example, an alkali or earth alkalinemetal carbonate, hydrogen carbonate or hydroxide, e.g. sodium carbonateor preferably sodium hydroxide, or an organic amine, e.g.N,N-diethylethanamine and the like, in a reaction-inert solvent such as,for example, an alkanol, e.g. methanol, ethanol, 2-propanol, 1-butanoland the like, a halogenated hydrocarbon, e.g. dichloromethane,trichloromethane and the like, an aromatic hydrocarbon, e.g. benzene,methylbenzene, dimethylbenzene and the like, or a mixture of saidsolvents, preferably at an elevated temperature, in particular thereflux temperature of the reaction mixture, ##STR9## (iv) N-alkylatingthe intermediate of formula (VI) with an alkylating reagent of formulaL--W (VII) wherein L is C₃₋₇ alkenyl as defined under formula (I) and Wrepresents a reactive leaving group such as halo or a sulfonyloxy group,in a manner known per se, i.e. in a reaction-inert solvent in thepresence of a base and optionally in the presence of an alkali metaliodide, at an elevated temperature, ranging from about 40° C. to thereflux temperature of the reaction mixture, preferably at about 50° C.,##STR10## (v) selectively reducing the nitrogroup in (VIII) with areducing agent to an amino group in a manner known per se, ##STR11##(vi) condensing the9-amino-6-halo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine of formula (IX)with carbon disulfide, 1,1'-carbonothionylbis[1H-imidazole], a xanthateand the like reagents, in a manner known per se, to a compound offormula (I), and optionally, if desired, convening the thus obtainedcompounds of formula (I) into therapeutically active non-toxic acidaddition salt forms by treatment with an acid, or conversely, convertingthe acid addition salt form into the free base with alkali; ##STR12##Reaction step (i) is preferably conducted by using enantiomerically pure1,2-diaminopropane protected on N¹ by a sulfonyl group, in particular,4-methylbenzenesulfonyl or 2,6-dimethylbenzenesulfonyl. The preferred(S)-enantiomers of the compounds of formula (I) are prepared from (S)-N¹-protected-1,2-diaminopropanes which are readily available fromcommercial (S)-1,2-diaminopropane by selective protection of thesterically least hindered primary amino group (reaction step o). Forexample, selective protection of N¹ can conveniently be effected by slowaddition of a sulfonyl halide to an excess of 1,2-diaminopropane at atemperature ranging from about -10° C. to about 10° C., preferably fromabout 0° C. to about 5° C. The nitrated starting material of formula(II) wherein W represents halo can conveniently be prepared by nitratinga symmetrical 2,6-dihalobenzylhalide following art-known nitratingprocedures. The corresponding starting materials of formula (II) whereinW represents a sulfonyloxy group are preferably prepared by nitrating asymmetrical 2,6-dihalobenzaldehyde, reducing the aldehyde to the alcoholand sulfonylating with a sulfonyl halide.

According to a preferred embodiment of the process of the presentinvention the deprotected amine of formula (V) is not isolated from thereaction mixture, but is cyclized immediately to the9-nitro-6-halo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine of formula (VI)by diluting said reaction mixture with an alkanol such as, for example,ethanol, 2-propanol, 1-butanol and the like, alkalinizing with a basesuch as an alkali metal carbonate or hydroxide, e.g. sodium or potassiumcarbonate or hydroxide and the like bases, and stirring and heating thethus obtained basic reaction mixture, preferably at the refluxtemperature. This one pot approach to reaction steps (ii) and (iii)excludes a number of manipulations and results in an increased yield.

In an interesting alternative, the intermediate of formula (IV) is notdeprotected but directly cyclized to the benzodiazepine of formula (XIV)by a procedure similar to that described in reaction step (iii), i.e. bytreating (IV) with a base, preferably at an elevated temperature.##STR13##

The intermediate of formula (XIV) may then be deprotected by hydrolysisas described in reaction step (ii) to yield an intermediate of formula(VI). ##STR14##

Thus steps (ii) and (iii) may well be conducted in reverse order.Alternatively, the protected benzodiazepine of formula (XIV) can also beN-alkylated with a reagent of formula (L--W) (VII) according to aprocedure given in reaction step (iv), yielding an intermediate offormula (XV). ##STR15##

The intermediate of formula (XV) may then be deprotected by hydrolysisas described in reaction step (ii) to yield an intermediate of formula(VIII). Thus reaction step (ii) may also be conducted after first havingconducted reaction steps (iii) and (iv).

The reaction steps (iv), (v) and (vi) of the present process are knownper se from, for example, EP-A-0,348,522 and WO-91/04255. TheN-alkylation procedure (iv) can conveniently be conducted in solventsuch as an aromatic hydrocarbon, e.g. methylbenzene, an alcohol, e.g.1-butanol, a ketone, e.g. acetone or preferably 4-methyl-2-pentanone, adipolar aprotic solvent, e.g. N,N-dimethylformamide,N,N-dimethylacetamide, dimethyl sulfoxide and the like, or a mixture ofsuch solvents. Appropriate bases for use in said process are alkalimetal carbonates or hydrogen carbonates, or preferably organic basessuch as, for example, N,N-diethylethanamine,N-(1-methyl-ethyl)-2-propanamine and the like. The reduction procedure(v) can conveniently be conducted by treating the nitro compound (VI)with platinum or Raney nickel catalyst in an alcohol, preferablymethanol, under a hydrogen atmosphere at room temperature and at normalpressure, or alternatively with Raney nickel catalyst and hydrazine atan elevated temperature, in particular at the reflux temperature of thereaction mixture. The ultimate cyclization step (vi) is preferablyconducted by treating intermediate (IX) with a thiocarbonyl generatingreagent as described in EP-A-0,348,522. For example, said cyclizationcan be conducted with carbon disulfide in an alcohol such as methanol,ethanol and the like, in the presence of a base such as sodium orpotassium hydroxide and the like, at an elevated temperature, inparticular at about 50° to 80° C. Alternatively, said cyclization canalso be conducted by treating (IX) with1,1'-carbonothionylbis-[1H-imidazole] in an alcohol such as ethanol,2-propanol and the like or in an ether such as tetrahydrofuran,1,1'-oxybisethane and the like, optionally at an elevated temperatureand under an inert atmosphere.

A viable alternative for converting the intermediates of formula (VI)into the compounds of formula (I) comprises the following reactionsteps:

(vii) reducing the nitroderivate of formula (VI) to an amino derivate(X) in a manner known per se, ##STR16## (viii) cyclizing the thusobtained 9-amino-6-halo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine (X) tothe corresponding8-halo-4,5,6,7-tetrahydro-5-methyl-imidazo[4,5,1-jk][1,4]benzodiazepin-2-one(XI) with a carbonyl generating reagent such as, for example, ethylchloroformate and the like in a manner known per se, and optionallyconvening (XI) into an acid addition salt form, ##STR17## (ix) conveningthe intermediate (XI) or an acid addition salt form thereof, into thecorresponding 2,8-dihaloimidazo[4,5,1-jk][1,4]benzodiazepine (XII) bytreatment with an excess of a halogenating reagent such as, for example,phosphorylchloride, and the like, at an elevated temperature, inparticular from about 75° C. to about 105° C., ##STR18## (x)N-alkylating the intermediate (XII) with an alkylating reagent offormula L--W (VII) as defined hereinabove in a reaction-inert solvent inthe presence of a base and optionally in the presence of an alkali metaliodide; and optionally further converting (XIII) into an acid additionsalt form, ##STR19## (xi) convening the dihalo intermediate (XIII) orpreferably an acid addition salt form thereof, into a compound offormula (I) in a manner known per se, i.e. by heating (XIII) withthiourea in an alcohol such as, for example, ethanol, 2-propanol and thelike, and optionally, convening the thus obtained compounds of formula(I) into therapeutically active non-toxic acid addition salt forms bytreatment with an acid, or conversely, convening the acid addition saltform into the free base with alkali; ##STR20## The alternative approachrepresented by reaction steps (vii-xi) is especially attractive by thefact that the integrity of the C₃₋₇ alkenyl group L, in particular theposition of the double bond, can be maintained effortlessly. Thereaction steps (vii), (viii), (ix) and (xi) are known per se from, forexample, EP-A-0,348,522 and WO-91/04255. The N-alkylation procedure (x)on intermediate (XII) is novel and can conveniently be conductedfollowing art-known procedures, such as the procedures described inreaction step (iv) hereinabove. A surprising effect in the ultimate step(xi) relates to the use of acid addition salt forms of (XIII): whereasthe base form reacts only sluggishly with thiourea, the acid additionforms react quite rapidly. This simple modification results in aconsiderably shortened reaction time.

The key intermediates of formula (III) and (IV) used in the processaccording to the present invention arc deemed novel. Consequently, thepresent invention also concerns enantiomerically pure intermediateshaving the formulae ##STR21## and acid addition salt forms thereof,wherein R represents halo, and

P represents a sulfonyl group or an acyl group.

Preferred key intermediates are those wherein

R represents chloro or bromo, and

P represents benzenesulfonyl, 4-methylbenzenesulfonyl or2,6-dimethylbenzenesulfonyl.

The following examples serve to further illustrate the present inventionwithout however limiting the same thereto. Unless otherwise stated, allparts therein are by weight.

EXPERIMENTAL PART Example 1

To 62.9 parts of (S)-1,2-propanediamine under a nitrogen atmosphere(temp. 0°-5° C.) was added dropwise over 7 hours a solution of 80.84parts of 4-methylbenzenesulfonyl chloride in 1689 parts ofdichloromethane. After stirring overnight at 20° C., the reactionmixture was washed with 250 parts of water (3x). The organic layer wasseparated, dried, filtered and evaporated. About 1 gram of the thusobtained product was recrystallized from 2-propanol. After cooling to 0°C., filtering and drying, about 0.30 parts of crystals suitable forseeding were obtained. The remainder of the product was dissolved in4-methyl-2-pentanol by heating just below the reflux temperature. Themixture was allowed to cool slowly and at about 30° C. was seeded withthe previously obtained crystals. After further cooling to 0° C., theprecipitate was filtered off and triturated with 2,2'-oxybispropane. Thecrystals were filtered off, dried in vacuo, yielding 50.75 parts (52.4%)of (S)-N-2-aminopropyl-4-methylbenzenesulfonamide; mp. 82°-86° C.;[α]_(D) ²⁰ =-1.10° (c=1% in methanol) (interm. 1)

Example 2

At 12° C., sulfuric acid (89 ml) was added to nitric acid (114 ml),giving solution 1. 2-chloromethyl-1,3-dichlorobenzene (1.45 mol) wasmelted in a vacuum oven at 50° C. (mp:36°-39° C.).2-chloromethyl-1,3-dichlorobenzene (1.45 mol) was added to sulfuric acid(829.2 ml) at 15° C., giving mixture 2 (precipitation occurred).Solution 1 was added dropwise to mixture 2 over a 35 min. period, at22°-25° C. (exothermic reaction, emulsification). The reaction mixturewas stirred for 90 min. at 23° C. The reaction mixture was poured outinto ice/water (2250 g/500 ml) (exothermic temperature rise to 22° C.).The mixture was stirred for 90 min. at 23° C. The precipitate wasfiltered off, washed with water and dried (vacuum;30° C.), yielding342.1 g (98.1%)of 1,3-dichloro-2-(chloromethyl)-4-nitrobenzene (interm.2).

Example 3

a) To a solution of 6.0 parts of intermediate (2) in 44.5 parts oftetrahydrofuran were added 5.82 parts of intermediate (1) and 3.04 partsof N,N-diethylethanamine. The whole was stirred for 45 hours at refluxtemperature. After cooling to room temperature, the reaction mixture wasfiltered. The filtrate was dried, filtered and evaporated. The residuewas taken up in dichloromethane and washed with water (3×). The organiclayer was dried, filtered and evaporated, yielding 10.81 parts (100%) of(S)-N-[2-[[(2,6-dichloro-3-nitrophenyl)methyl]amino]propyl]-4-methylbenzenesulfonamide; mp. 85°-88° C.; [α]_(D)²⁰ =+9.15° (c=1% in methanol) interm.3).

b) To a solution (20° C.) of 2 parts of(2,6-dichloro-3-nitrophenyl)methanol methanesulfonate in 26.6 parts ofdichloromethane were added dropwise 0.68 parts of N,N-diethylethanamineand a solution of 1.52 parts of intermediate (1) in 13.3 parts ofdichloromethane. After stirring for 24 hours at reflux temperature, thereaction mixture was washed with water (3×). The organic layer wasseparated, dried, filtered and evaporated. The product was dried invacuo at 50° C., yielding 2.77 parts (96.1%) of(S)-N-[2-[[(2,6-dichloro-3-nitrophenyl)methyl]amino]propyl]-4-methylbenzenesulfonamide(interm. 3).

Example 4

To a mixture of 5 parts of intermediate (3) and 11.7 parts of sulfuricacid were added dropwise 1.15 parts of water. After stirring for 24hours at 100° C. and cooling, there were added 33.25 parts ofdichloromethane. The reaction mixture was cooled to 0° C. and there wasadded water (temp. 0°-5° C.). The reaction mixture was basified withNaOH. The aqueous layer was separated and extracted withdichloromethane. The combined organic layers were dried, filtered andevaporated. The residue was convened into the dihydrochloride salt in2-propanol saturated with hydrochloric acid. The product was filteredoff and dried, yielding 3.34 parts (82.3%) of (S)-N²-[(2,6-dichloro-3-nitrophenyl)methyl-1,2-propanediamine dihydrochloride(interm. 4).

Example 5

a) To a solution of 2 parts of intermediate (4) in 11.7 parts of2-propanol were added dropwise 2.88 parts of N,N-diethylethanamine.After refluxing for 10 hours, the reaction mixture was evaporated anddried in vacuo at 50° C. The residue was partitioned betweendichloromethane and water. Then there were added a few drops ofN,N-diethylethanamine until pH>9. The organic layer was separated,washed with water, dried, filtered and evaporated, yielding 1.32 parts(95.9%) of(S)-6-chloro-2,3,4,5-tetrahydro-3-methyl-9-nitro-1H-1,4-benzodiazepine(interm.5).

b) A solution of 49 parts of intermediate (3) in 116.8 parts of sulfuricacid was warmed up to 80° C. Then there were added dropwise 11.3 partsof water and the whole was stirred for 30 hours at 100° C. After coolingthere were added 222.3 parts of 2-propanol and portionwise 144.1 partsof sodium carbonate. The whole was stirred for 5 hours at refluxtemperature. The reaction mixture was evaporated and the residue waspartitioned between dichloromethane and water. The whole was filteredand the organic layer was separated and washed with water (2×). Thecombined organic layers were dried, filtered and evaporated at 50° C.,yielding 23.74 parts (86.7%) of(S)-6-chloro-2,3,4,5-tetrahydro-3-methyl-9-nitro- 1H-1,4-benzodiazepine(interm. 5).

Example 6

A mixture of 1 part of intermediate (5) and 59.25 parts of methanol washydrogenated at normal pressure and at 20° C. in the presence of 0.082parts of platinum-on-charcoal catalyst 5%. After the calculated amountof hydrogen was taken up, the catalyst was filtered off overdiatomaceous earth and the filtrate was evaporated. The product wasdried in vacuo at 45° C., yielding 0.87 parts (99.3%) of(S)-6-chloro-2,3,4,5-tetrahydro-3-methyl -1H-1,4-benzodiazepin-9-amine(interm. 6).

Example 7

To a cooled mixture (ice-bath) of 0.77 parts of sodium carbonate and0.70 parts of intermediate (6) in 0.66 ml of propylene glycol monomethylether were added dropwise 0.79 parts of ethyl chloroformate. The wholewas stirred for 2 hours at 20° C. and then refluxed for 20 hours. Thereaction mixture was cooled to 80° C. and 2.64 parts of NaOH 50% wereadded. Refluxing was continued for 24 hours. After cooling (50° C.),water was added and the whole was stirred for 1 hour. The aqueous layerwas separated and extracted with polyglycol monomethyl ether and thecombined organic layers were neutralized with HCl, yielding 0,785 parts(99.9%) of(S)-8-chloro-4,5,6,7-tetrahydro-5-methylimidazo[4,5,1-jk][1,4]benzodiazepin-2(1H)-one(interm. 7).

Example 8

13 parts of intermediate (7) was converted into the hydrochloride saltin 2-propanol saturated with hydrochloric acid. The precipitate wasfiltered off and washed with 2-propanol, yielding 13.5 parts (90.0%) ofproduct. The mother liquor was evaporated and dried at 50° C., yieldinganother 0.58 parts (3.8%) of product. Total yield: 14.08 parts (93.9%)of(S)-8-chloro-4,5,6,7-tetrahydro-5-methylimidazo[4,5,1-jk][1,4]-benzodiazepin-2(1H)-onemonohydrochloride (interm. 8).

Example 9

At 20° C., 2 parts of intermediate (8) were suspended in 29.7 parts ofphosphoryl chloride. The suspension was warmed up to 90° C. and therewere added another 42.6 parts of phosphoryl chloride. The reactionmixture was filtered at 20° C. and the filtrate was evaporated. Theresidue was taken up in 180 parts of ethyl acetate. At 0°-5° C. themixture was basified with a solution of sodium hydrogen carbonate inwater and stirring was continued for 1 hour at this temperature. Thewhole was filtered and washed with ethyl acetate. The aqueous layer wasseparated and re-extracted with ethyl acetate. The combined organiclayers were washed with water, dried, filtered and evaporated, yielding1.07 parts (57.3%) of(S)-2,8-dichloro-4,5,6,7-tetrahydro-5-methyl-imidazo[4,5,1-jk][1,4]benzodiazepine(interm. 9).

Example 10

To a stirred mixture of 5.5 parts of intermediate (9), 89.1 parts ofdichloromethane, 3.42 parts of sodium carbonate, 18.8 parts ofN,N-dimethylformamide and 3.57 parts of potassium iodide were addeddropwise 2.39 parts of N,N-diethylethanamine and 41.94 parts1-chloro-3-methyl-2-butene in 65.25 parts of methylbenzene. Afterrefluxing for 48 hours, the reaction mixture was washed with water (5×).The organic layer was separated, dried, filtered and evaporated. Theresidue wag converted into the hydrochloride salt in 2-propanolsaturated with hydrochloric acid. The salt was filtered off at 0°-5° C.and dried in vacuo at 29° C., yielding 5.18 parts (66.8%) of product.The mother liquor was stirred for 24 hours at 20° C., filtered off,washed and dried, yielding another 0.49 parts (6.3%)of product. Totalyield:5.67 parts (73.1%)of (S)-2,8-dichloro-4,5,6,7-tetrahydro-5-methyl-6-(3-methyl-2-butenyl)imidazo[4,5,1-jk][1,4]-benzodiazepine dihydrochloride (interm. 10).

Example 11

a) To a solution (20° C.) of 2.5 parts of intermediate (10) in 12.6parts of ethanol were added 0.53 parts of thiourea. After stirring for1.5 hours at reflux temperature, the reaction mixture was cooled to0°-5° C. and filtered off at 0° C. The residue was dried in vacuo at 30°C., yielding 1.70 parts (75.4%) of(-)-(S)-8-chloro-4,5,6,7-tetrahydro-5-methyl-6(3-methyl-2-butenyl)imidazo[4,5,1-jk][1,4]benzodiazepin-2(1H)-thionemonohydrochloride; mp. 230° C.; [α]_(D) ²⁰ =-76.61° (c=1% in methanol)(comp. 1).

b) 0.5 Parts of compound (1) were partitioned between dichloromethaneand water. The whole was basified with NH₄ OH. The organic layer wasseparated, dried, filtered and evaporated. The product was dried invacuo at 40° C., yielding 0.43 parts (95.7%) of(+)-(S)-8-chloro-4,5,6,7-tetrahydro-5-methyl-6-(3-methyl-2-butenyl)imidazo[4,5,1-jk]-[1,4]benzodiazepin-2(1H)-thione;mp. 160° C.; [α]_(D) ²⁰ =+9.97° (c=1% in methanol (comp. 2).

Example 12

To a mixture of 11.30 parts of intermediate (5), 56 parts of4-methyl-2-pentanone, 3.88 parts of potassium iodide and 14.85 parts ofsodium carbonate were added dropwise 119.7 parts of1-chloro-3-methyl-2-butene. After refluxing for 3 hours, the reactionmixture was diluted with water. The whole was stirred for 30 minutes.The aqueous layer was separated and re-extracted with4-methyl-2-pentanone. The combined organic layers were dried, filteredand evaporated. The residue was purified by column chromatography(silicagel: eluens CH₂ Cl₂), yielding 7.72 parts (53.3%)(S)-6-chloro-2,3,4,5-tetrahydro-3-methyl-4-(3-methyl-2-butenyl)-9-nitro-1H-1,4-benzodiazepine; mp. 60°-62° C.; [α]_(D) ²⁰ =+118.53° (c=1% inmethanol) (interm. 11).

In a similar way there were prepared:

[S,(Z)]-4-(2-butenyl)-6-chloro-2,3,4,5-tetrahydro-3-methyl-9-nitro-1H-1,4-benzodiacepine(interm. 13);

(S)-6-chloro-2,3,4,5-tetrahydro-3-methyl-4-(2-methyl-2-propenyl)-9-nitro-1H-1,4-benzodiazepine(interm. 14);

[S,(E)]-4-(2-butenyl)-6-chloro-2,3,4,5-tetrahydro-3-methyl-9-nitro-1H-1,4-benzodiazepine(interm. 15);

[S,(E)]-6-chloro-4-(2-ethyl-2-butenyl)-2,3,4,5-tetrahydro-3-methyl-9-nitro-1H-1,4-benzodiazepine(interm. 16);

[S,(Z)]-6-chloro-2,3,4,5-tetrahydro-3-methyl-9-nitro-4-(2-pentenyl)-1H-1,4-benzodiazepine(interm. 17);

[S,(Z)]-6-chloro-4-(3-hexenyl)-2,3,4,5-tetrahydro-3-methyl-9-nitro-1H-1,4-benzodiazepine(interm. 18);

[S,(E)]-6-chloro-4-(2-hexenyl)-2,3,4,5-tetrahydro-3-methyl-9-nitro-1H-1,4-benzodiazepine (interm. 19);

[S,(E)]-6-chloro-4-(3-hexenyl)-2,3,4,5-tetrahydro-3-methyl-9-nitro-1H-1,4-benzodiazepine(interm. 20);

(S)-4-(3-butenyl)-6-chloro-2,3,4,5-tetrahydro-3-methyl-9-nitro-1H-1,4-benzodiazepine(interm. 21 ); and

(S)-6-fluoro-2,3,4,5-tetrahydro-3-methyl-4-(3-methyl-2-butenyl)-9-nitro-1H-1,4-benzodiazepine(interm. 22).

Example 13

a) A solution of 2.16 parts of intermediate (11) in 67.2 parts ofethanol was hydrogenated overnight at normal pressure and roomtemperature in the presence of a few parts of Raney nickel. The catalystwas filtered off and washed with ethanol. The combined filtrates wereevaporated and the residue was washed with water, dried, filtered andevaporated, yielding 1.9.6 parts (100%) of(S)-6-chloro-2,3,4,5-tetrahydro-3-methyl-4-(3-methyl-2-butenyl)-1H-1,4-benzodiazepin-9-amine(interm. 12) b) To a solution of 0.5 parts of intermediate (11) inmethanol there were added 0.2 parts of Raney nickel. To the resultingsuspension there was added a solution of 0.35 parts of hydrazine in asmall amount of methanol and the reaction mixture was refluxed for 1.5hours under an inert atmosphere. After cooling, the catalyst wasfiltered off and the filtrate was evaporated, yielding(S)-6-chloro-2,3,4,5-tetrahydro-3-methyl-4-(3-methy-2-butenyl)-1H-1,4-benzodiaepin-9-amine(interm. 12). In a similar way there were prepared:

(S)-6-chloro-2,3,4,5-tetrahydro-3-methyl-4-(2-methyl-2-propenyl)-1H-1,4-benzodiazepin-9-amine(interm. 23);

[S,(E)]-4-(2-butenyl)-6-chloro-2,3,4,5-tetrahydro-3-methyl-1H-1,4-benzodiazepin-9-amine(interm. 24);

(S)-6-fluoro-2,3,4,5-tetrahydro-3-methyl-4-(3-methyl-2-butenyl)-1H-1,4-benzodiazepin-9-amine(interm. 25);

[S,(E)]-6-chloro-4-(2-ethyl-2-butenyl)-2,3,4,5-tetrahydro-3-methyl-1H-1,4-benzodiazepin-9-amine(interm. 26);

[S,(Z)]-6-chloro-2,3,4,5-tetrahydro-3-methyl-4-(2-pentenyl)-1H-1,4-benzodiazepin-9-amine(interm. 27);

[S,(Z)]-6-chloro-4-(3-hexenyl)-2,3,4,5-tetrahydro-3-methyl-1H-1,4-benzodiazepin-9-amine(interm. 28); and

[S,(Z)]-4-(2-butenyl)-6-chloro-2,3,4,5-tetrahydro-3-methyl-1H-1,4-benzodiazepin-9-amine(interm. 29).

c) Lithium aluminum hydride (30 ml) was stirred under argon flow.Intermediate (20) (0.005 mol) was dissolved in tetrahydrofuran (15 ml)and this solution was added dropwise to the reaction mixture (colourchange; slight exothermic reaction). The reaction mixture was allowed towarm up to room temperature and was stirred for 6 hours. 3N NaOH (2.55ml) was added cautiously and dropwise (foaming, colour change;exothermic reaction). The reaction mixture was stirred for 0.5 hours andfiltered over dicalite. The filtrate was evaporated. The residue (1.58g; oil) was purified by flash column chromatography over silica gel(eluent: CH₂ Cl₂ /CH₃ OH 100/0 upgrading to 98/2). The pure fractionswere collected and evaporated, yielding 0.93 g (63%) of

[S,(E)]-6-chloro-4-(3-hexenyl)-2,3,4,5-tetrahydro-3-methyl-1H-1,4-benzodiazepin-9-amine(interm. 30);

In a similar way there were prepared:

[S,(E)]-6-chloro-4-(2-hexenyl)-2,3,4,5-tetrahydro-3-methyl-1H-1,4-benzodiazepin-9-amine(interm. 31 ); and

(S)-4-(3-butenyl)-6-chloro-2,3,4,5-tetrahydro-3-methyl-1H-1,4-benzodiazepin-9-amine(interm. 32)

Example 14

a) A mixture of 0.295 parts of intermediate (12), 0.0056 parts ofpotassium hydroxide, 0.79 parts of ethanol and 0.06 parts of carbondisulfide was stirred for 18 hours at 60° C. After cooling, there wasadded trichloromethane and the whole was filtered. The filtrate wasevaporated and the residue was purified by colomn chromatography(silicagel; eluens: CHCl₃ /CH₃ OH; 99.5:0.5). The eluent of the desiredfraction was filtered and evaporated and the residue was triturated in3.95 parts of acetonitrile under a nitrogen atmosphere. The product wasfiltered off and dried under a nitrogen atmosphere, yielding 0.308 parts(91.1%) of(+)-(S)-8-chloro-4,5,6,7-tetrahydro-5-methyl-6-(3-methyl-2-butenyl)imidazo-[4,5,1-jk][1,4]benzodiazepin-2(1H)-thione(comp. 2). b) To a solution of 1.69 parts of intermediate (12) in 14.0parts of 2-propanol there were added 1.18 parts of1,1'-carbonothionylbis[1H-imidazole]. The whole was homogenized and thenleft for 1/2 hour to crystallize. The product was filtered off, washedwith 2-propanol and dried in vacuo, yielding 0.92 parts (47.6%). Themother liquor was stirred overnight at 0°-5° C. A second productfraction was filtered off, washed and dried, yielding 0.26 parts(13.5%). Total yield: 1.18 parts (61.1%) of(+)-(S)-8-chloro-4,5,6,7-tetrahydro-5-methyl-6-(3-methyl-2butenyl)imidazo-[4,5,1-jk][1,4]benzodiazepin-2(1H)-thione; [α]α_(D) ²⁰ =+8.98° (conc.=1% inmethanol) (comp 2). c) To a flask under argon was added 1.75 g ofintermediate (12) in 35 ml of tetrahydrofuran and 1.40 g of1,1'-carbonothionylbis[1H-imidazole]. The reaction mixture was refluxedfor 0.5 hours, the solvent evaporated and the residue flashchromatographed with 0.5% CH₃ Oh/CH₂ Cl₂ to give 2 g of product. Onerecrystallization with ethanol gave 1.03 g (54%) of(+)-(S)-8-chloro-4,5,6,7-tetrahydro-5-methyl-6-(3-methyl-2-butenyl)imidazo-[4,5,1-jk][1,4]benzodiazepin-2(1H)-thione;mp. 163.3° C. (comp. 2).

In a similar way were prepared:

(+)-[S,(Z)]-8-chloro-6-(3-hexenyl)-4,5,6,7-tetrahydro-5-methylimidazo-[4,5,1-jk][1,4]benzodiazepin-2(1H)-thione; mp. 139.40° C.;

[α]_(D) ²⁰ =+9.84° (conc.=0.64% in trichloromethane) (comp. 3);

(+)-[S,(E)]-8-chloro-6-(2-hexenyl)-4,5,6,7-tetrahydro-5-methylimidazo-[4,5,1-jk][1,4]benzodiazepin-2(1H)-thione; 142.9° C.;

[α]_(D) ²⁰ =+3.54° (conc.=0.48% in methanol) (comp. 4);

(+)-[S,(E)]-8-chloro-6-(3-hexenyl)-4,5,6,7-tetrahydro-5-methylimidazo-[4,5,1-jk][1,4]benzodiazepin-2(1H)-thione; mp. 144.4° C.;

[α]_(D) ²⁰ =+12.46° (conc.=0.69% in methanol) (comp. 5);

(+)-(S)-6-(3-butenyl)-8-chloro-4,5,6,7-tetrahydro-5-methylimidazo-[4,5,1-jk][1,4]benzodiazepin-2(1H)-thione; mp. 170.4° C.;

[α]_(D) ²⁰ =+6.11° (conc.=0.36% in methanol) (comp. 6);

(+)-[S,(Z)]-6-(2-butenyl)-8-chloro-4,5,6,7-tetrahydro-5-methylimidazo-[4,5,1-jk][1,4]benzodiazepin-2(1H)-thione; mp. 159.6° C.;

[α]_(D) ²⁰ =+12.67° (conc.=0.1% in methanol) (comp. 7);

(+)-(S)-8-fluoro-4,5,6,7-tetrahydro-5-methyl-6-(3-methyl-2-butenyl)imidazo-[4,5,1-jk][1,4]benzodiazepin-2(1H)-thione; mp. 172.1 ° C.;

[α]_(D) ²⁰ =+5° (conc.=1% in methanol) (comp. 8);

(+)-[S,(E)]-6-(2-butenyl)-8-chloro-4,5,6,7-tetrahydro-5-methylimidazo-[4,5,1-jk][1,4]benzodiazepin-2(1H)-thione; 159.2° C.;

[α]_(D) ²⁰ =+1.2° (conc.=0.83% in methanol) (comp. 9);

(+)-[S,(E)]-8-chloro-6-(2-ethyl-2-butenyl)-4,5,6,7-tetrahydro-5-methylimidazo-[4,5,1-jk][1,4]benzodiazepin-2(1H)-thione; mp. 163.6° C.;

[α]_(D) ²⁰ =+17.7° (conc. =0.1% in methanol) (comp. 10);

(+)-[S,(Z)]-8-chloro-4,5,6,7-tetrahydro-5-methyl-6-(2-pentenyl)imidazo-[4,5,1-jk][1,4]benzodiazepin-2(1H)-thione; mp. 143.1 ° C.;

[α]_(D) ²⁰ =+9.19° (conc.=0.1% in methanol) (comp. 11); and

(-)-(S)-8-chloro-4,5,6,7-tetrahydro-5-methyl-6-(2-methyl-2-propenyl)imidazo-[4,5,1-jk][1,4]benzodiazepin-2(1H)-thione monohydrochloride; mp. 207.6° C.;

[α]_(D) ²⁰ =-33.01° (conc.=0.1% in methanol) (comp. 12).

We claim:
 1. A process for preparing an enantiomerically pure8-halo-4,5,6,7-tetrahydro-5-methylimidazo[4,5,1-jk][1,4]benzodiazepin-2-(1H)-thione of the formula: ##STR22## or apharmaceutically acceptable acid addition salt form thereof, wherein: Rrepresents halo; and L represents C₃₋₇ alkenyl,wherein said processcomprises the steps of: (a) selectively protecting enantiomerically pure1,2-diaminopropane by reaction with a protecting group of the formulaP--W wherein P represents a protecting group selected from the groupconsisting of sulfonyl and acyl, and W represents a reactive leavinggroup selected from the group consisting of halo and sulfonyloxy, toproduce an intermediate of Formula (III): ##STR23## wherein P is asdefined above: (b) reacting a 2,6-dihalo-3-nitrobenzyl derivative of theformula: ##STR24## wherein R represents halo and W represents a reactiveleaving group selected from the group consisting of halo andsulfonyloxy, with an enantiomerically pure N¹ -protected1,2-diaminopropane derivative of Formula (III) in an inert reactionvehicle in the presence of a base, to produce an intermediate of theformula: ##STR25## wherein P and R are as defined above; (c)deprotecting the thus obtained intermediate of Formula (IV) in an acidicmedium, to produce an intermediate of the formula: ##STR26## or its acidaddition salt, wherein R is as defined above; (d) cyclizing theintermediate of Formula (V) or its acid addition salt by treatment witha base in an inert reaction vehicle at an elevated temperaturesufficient to effect the cyclization, to thereby produce abenzodiazepine of the formula: ##STR27## wherein R is as defined above;(e) N-alkylating the benzodiazepine of Formula (VI) with an alkylatingreagent of formula L--W wherein L is C₃₋₇ alkenyl and W is a reactiveleaving group selected from the group consisting of halo andsulfonyloxy, in an inert reaction vehicle in the presence of a base atan elevated temperature sufficient to effect the N-alkylation, toproduce thereby an intermediate of Formula (VIII): ##STR28## wherein Land R are as defined above; (f) selectively reducing the nitro group inthe compound of Formula (VIII) by treatment with a reducing agent, toproduce an intermediate of Formula (IX): ##STR29## wherein L and R areas defined above; and (g) condensing the intermediate of Formula (IX)with carbon disulfide, 1,1'-carbonothionylbis or a xanthate, to producea compound of Formula (I).
 2. A process according to claim 1 wherein thecompound of formula (I) has the formula ##STR30##
 3. A process accordingto claim 2 wherein R represents chloro or bromo; and L represents3-methyl-2-butenyl or 3-ethyl-2-pentenyl.
 4. A process according toclaim 3 wherein the compound of formula (I) is(S)-8-chloro-4,5,6,7-tetrahydro-5-methyl-6-(3-methyl-2-butenyl)imidazo[4,5,1-jk]-[1,4]benzodiazepine-2(1H)-thione or an acid addition salt thereof.5. A process according to claim 1 wherein a one pot approach to reactionsteps (c) and (d) is employed.
 6. A process according to claim 1 whereinreaction steps (c) and (d) are conducted in reverse order.
 7. Theprocess of claim 1 wherein the N-alkylation of step (e) is carried outin the presence of an alkali metal iodide.
 8. A process for preparing anenantiomerically pure 8-halo-4,5,6,7-tetrahydro-5-methylimidazo[4,5,1-jk][1,4]benzodiazepin-2--(1H)-thione of the formula: ##STR31## ora pharmaceutically acceptable acid addition salt form thereof, wherein:R represents halo; andL represents C₃₋₇ alkenyl,wherein said processcomprises the steps of: (a) selectively protecting enantiomerically pure1,2-diaminopropane by reaction with a protecting group of the formulaP--W wherein P represents a protecting group selected from the groupconsisting of sulfonyl and acyl, and W represents a reactive leavinggroup selected from the group consisting of halo and sulfonyloxy, toproduce an intermediate of Formula (III): ##STR32## wherein P is asdefined above: (b) reacting a 2,6-dihalo-3-nitrobenzyl derivative of theformula: ##STR33## wherein R represents halo and W represents a reactiveleaving group selected from the group consisting of halo andsulfonyloxy, with an enantiomerically pure N¹ -protected1,2-diaminopropane derivative of Formula (III) in an inert reactionvehicle in the presence of a base, to produce an intermediate of theformula: ##STR34## wherein P and R are as defined above; (c)deprotecting the thus obtained intermediate of Formula (IV) in an acidicmedium, to produce an intermediate of the formula: ##STR35## or its acidaddition salt, wherein R is as defined above; (d) cyclizing theintermediate of Formula (V) or its acid addition salt by treatment witha base in an inert reaction vehicle at an elevated temperaturesufficient to effect the cyclization, to thereby produce abenzodiazepine of the formula: ##STR36## wherein R is as defined above;(e) reducing the benzodiazepine of Formula (VI) by treatment with areducing agent to produce an amino derivative of the formula: ##STR37##wherein R is as defined above; (f) cyclizing the amino derivative ofFormula (X) with a carbonyl generating reagent to produce a compound ofthe formula: ##STR38## wherein R is as defined above; (g) treating thecompound of Formula (XI) or an acid addition salt thereof with ahalogenating reagent at an elevated temperature sufficient to halogenatesaid compound of Formula (XI) to produce a compound of the formula:##STR39## wherein R is as defined above and "halo" represents a halogroup; (h) N-alkylating the compound of Formula (XII) with an alkylatingreagent of formula L--W wherein L is C₃₋₇ alkenyl and W is a reactiveleaving group in an inert reaction vehicle in the presence of a base atan elevated temperature sufficient to effect the N-alkylation, forproduce thereby a compound of the formula: ##STR40## wherein R, L andhalo are as defined above; and (i) reacting the compound of Formula(XIII) or an acid addition salt thereof with thiourea in an alcohol atan elevated temperature sufficient to produce a compound of Formula (I).9. A process according to claim 8 wherein the compound of formula (I) is(S)-8-chloro-4,5,6,7-tetrahydro-5-methyl-6-(3-methyl-2-butenyl)imidazo[4,5,1-jk]-[1,4]benzodiazepine-2(1H)-thioneor an acid addition salt thereof.
 10. The process of claim 8 wherein theN-alkylation of step (h) is carried out in the presence of an alkalimetal iodide.